Multiple myeloma (MM) is still incurable - causing the death of 10,000 Americans annually. Currently, glucocorticoids and the proteasome-inhibiting drug PS-341 (Bortezomib/Velcade) rank among the most effective agents in myeloma therapy. Given that MM is a radiosensitive malignancy, radiation-based combination strategies that incorporate these cytotoxic drugs are likely to lead to effective regimens. Our overall hypothesis is that glucocorticoids and proteasome inhibitors, when combined with radiotherapy, will attenuate constitutive and radiation-induced NF?B activation, thereby inhibiting downstream IL6 synthesis, leading to the radiosensitization of myeloma cells, and inhibiting the development of drug resistance. In vitro studies will use established myeloma cell lines and patient samples co-cultured with bone marrow stromal cells. The syngeneic, orthotopic 5TGM1 myeloma model will be used for in vivo studies. In Aim 1 we will evaluate the ability of combined dexamethasone treatment and 153-Sm-EDTMP radiotherapy to selectively enhance the therapeutic index for MM by inhibiting IL6 expression. In Aim 2 we will explore the effects of combined dexamethasone, PS-341 and 153-Sm-EDTMP treatment with respect to enhancing the therapeutic index for MM, via inhibition of NF?B-induced IL6 expression. In Aim 3 we will determine the effects of IL6 synthesis in the bone marrow microenvironment on the induction of cellular antioxidants, and identify the consequences with respect to the development of myeloma-cell resistance to drug treatment. The goal of this proposal is to develop radiation-based combination therapies involving cytotoxic drugs to selectively radiosensitize myeloma cells such that the myeloma-cell drug resistance in the bone marrow microenvironment is inhibited. Such studies will provide mechanistic insights into why the frontline therapies for myeloma are failing, and also establish a strong biochemical rationale for the design of a Phase I/II trial in near future with a good chance of improving the overall survival and quality of life in myeloma patients.